Feature Articles

Perspectives on Alzheimer’s disease

Alzheimer’s disease is a commonly encountered pa ent case by medical students. However, many students struggle to see the person beyond the disease. This essay o ers a di erent perspec ve into Alzheimer’s disease, a deeper understanding that is crucial towards fostering more empathe c, a en ve and compassionate pa ent interac ons.

Since the start of my medical studies, I have found the disease process of Alzheimer’s disease an emotional and physiological enigma. However, it is the case of Clarice that profoundly impacted a deeper insight into the complexity of a life lived with Alzheimer’s disease.

Clarice has been living with Alzheimer’s disease since the death of her husband eleven years ago. Her family helplessly witness as she gradually loses any semblance of order and familiarity in her life. At first, she disguised her confusion through a veil of phrases, covering up her forgetfulness with laughter “Of course I knew that, I was only joking.” Alzheimer’s disease drowned Clarice within waves of confusion, muddling up her thoughts and blending the faces she was surrounded by all of her life with faces of strangers as she tried to tread water in the relentless current. She always wore a smile and came accompanied with jokes and quirky musings. She became known by eccentric catch phrases “How do you spell nachas (happiness)?” that she asked of her grandchildren. To which they answered melodiously “C L A R I C E”. At every family gathering, she tapped her glass with a fork and announced, “with tears in my eyes, I just want to say how special it is to be here, no itching or bitching, just all together, as a family.” As she left, she gathered everyone together and departed with famous final words “Go well, go shell, but don’t go to hell”.

“Go well, go shell, but –“,
“Don’t ring the bell!”
“Don’t say farewell!” her family tried to interject.
“No.” she confirmed with a cheeky grin, “Don’t go to hell!”

At Friday night meals, Clarice’s thirteen grandchildren said the Jewish blessing over food in chronological order from eldest to youngest. With much humour, Clarice would exclaim “Our Father, the holy spirit…” and proceed to tap out the cross on her body, reminding them of her rich childhood. Having attended a Catholic boarding school as a young Jewish girl, the daily prayers and hymns have stayed with her into old age. Her family loved her Zulu exclamations “saqua bona wena”, to which they replied in their own made up language, matching the sounds of her youth.

As her cognition declined, her honesty and humour sharpened and the kindness, love, and compassion that overflowed from her heart amplified. At times, her honesty was brutal, revealing hidden layers about the people surrounding her. No longer aware of social cues or the importance of privacy, she pointed out the sad man sitting by himself, or the distressed woman lost in thought. While sometimes uncomfortable, such honesty only exposed her caring and sensitive nature. She was apt at identifying someone’s hidden sadness, unbeknownst to anyone else, and quick to enquire why, offering her ear and heart.

If her family had visitors at their weekly Shabbat meals who showed signs of fragility, Clarice was the first to get up and help. “Can I help you up from the table?” “You stay put and I’ll get your food for you, what would you like?” The irony of such moments was heartrending, her ability to help those who were physically unwell when she wasn’t able, nor was anyone else, to help the illness that overwhelmed her mind.

As time gradually undid the threads that held together the clarity of Clarice’s mind, her sentences slipped into nonsensical musings. Moments of her childhood featured more frequently as she lost track of time. She referred to herself as a little girl, telling her adult children that she had to go home lest her parents worry where she was.

Yet, there were moments of pure happiness that peaked out occasionally. Her genuine awe as she watched the sunsets that showered her balcony and the raw happiness and surprise she had when her granddaughters kissed her on the cheek for a ‘selfie’, were moments of bliss. Her family learnt what made her happy and was able to tap into such experiences to change solemn moments into happier ones. The more they became desensitised to the tragedy of her illogical talk and the more they learnt how to laugh with her rather than cry, the more they were able to find joy and beauty in her quirky musings and disjointed sentences. The more they distanced themselves from her disease, the more they appreciated her presence, her warmth, and her unconditional love.

Clarice is not and never has been my patient. She is my grandmother, my Bobba. At the same time that I was dealing with the sudden deterioration of my Bobba’s cognition, I started my geriatrics placement at the hospital. The internal struggle that I felt as I grappled with my Bobba’s decline gave me a new perspective of the patients I met during that term.

Patient labels transitioned from ‘the demented old lady with delirium secondary to constipation’ to ‘the retired teacher and grandmother of seven suffering with …’. I found myself with a newfound depth of empathy and patient centered care. This gave me a greater understanding of the underlying disease processes of the patients as my passion for their wellbeing led me to deeper investigations of their conditions. The lessons I learnt from communicating with my Bobba, especially in her moments of stress and confusion, enabled me to connect to the geriatric patients with greater patience, tolerance, and appreciation. I found that I was able to implement the ‘tricks’ I learnt from soothing my Bobba to soothing distressed, agitated, and scared patients. The timing of my geriatrics placement was no coincidence but a treasured journey that transformed the blanket of grief, loss, and regret that plagued my mind, with acceptance, gratitude, and understanding. It was emotionally draining to be confronted with the exact challenges that I tried to distance myself from in my personal life every day at placement. Nonetheless, witnessing so many people in the same circumstance as my Bobba and my family also brought solace and comfort.

One moment I will never forget was walking into a very disorientated woman’s room; she was 63 years old and had early onset Alzheimer’s disease. She lay in bed with her 40-year-old daughter, who cuddled her while stroking her hair and placating her with kind words “Don’t worry mum, I’m here, everything’s going to be alright”. I left hospital that day and went straight to my Bobba’s home. Although I sensed that she didn’t know exactly who I was that day, I felt her love for me and as we sat together cuddled up on the couch, I found pleasure in the complex simplicity of love and togetherness that persists, and perhaps even strengthens, in the face of suffering and adversity.

Just like the 40-year-old daughter, I remember my own mother placating my Bobba by likening her confusion to a car ride, telling her that she can simply shut off, relax, and enjoy the ride, knowing with confidence that she was being looked after. That although she was in the passenger seat, she could trust in the fact that the driver had planned the journey meticulously ahead with love and care.  When my mother suffered herself, overwhelmed by hopelessness and pain, I remember my aunty, my mother’s younger sister, telling her that it was better to laugh, to simply shut off, relax, and enjoy the ride herself. As my aunty so aptly put it, “we have to laugh, for if we don’t laugh, then we’ll just cry.”

We chose to ignore the ugliness of the disease and to find joy in the benevolent absurdity of my Bobba’s behaviour. We laughed in the lift of crowded people when my Bobba interrupted the silence singing ‘Ba Ba Black Sheep’. We laughed when my Bobba plaited my friends’ hair together as they sat on the couch. We laughed when my Bobba walked up to the stranger engrossed in her book to sit down beside her and engage in conversation as if they were lifelong friends. We laughed so much with my Bobba until we laughed so much that we cried. And I thought of all those times we ran around as small children, my Bobba warning us “too much laughter ends in crying”. Yet, now we reversed this, we turned all our crying into laughter. And we were so much happier.

Alzheimer’s disease teaches us to savour every minute spent with those we love. It sensitises us to those extraordinary moments of pure joy. It clears out the complexity of the recent past and future to make way for the serenity of the present. It peels away the shell of the mind only to reveal the perfection of the soul – what a beautiful force to be around.

Conflicts of Interest

None declared.

This article was first published in the Australian Journal of Dementia Care ( Vol 5 No 6 December/January 2016-2017. Reprinted here with the permission of Hawker Publications Australia Pty Ltd.



Lacklustre performance: drugs targeting β-amyloid in Alzheimer’s disease

The Alzheimer’s Association International Conference (AAIC) is the largest gathering of the Alzheimer’s disease (AD) research community in the world, and provides a unique forum for the discussion of ideas and dissemination of knowledge. One of the key concepts grappled by the AD research community at AAIC 2016 in Toronto, Canada, was the validity of the amyloid hypothesis.

It is generally accepted that the accumulation of b-amyloid (Ab), particularly Ab40-42, in the extracellular spaces around neurons as amyloid plaques is central to the pathogenesis of AD. This idea is expressed in the ‘amyloid cascade hypothesis’ [1,2]. It thus follows that by reducing the production of Ab or eliminating the amyloid plaques from the brain, the progression of disease could be slowed, halted, or even reversed [3]. Alzheimer’s disease is the most important cause of dementia, which affects a staggering 40 million people worldwide, a number which is predicted to double every 20 years until 2050 [4]. Therefore, achieving prevention, or even just slowing of disease progression, would have a significant impact on morbidity, mortality, and burden on healthcare systems worldwide.

Hence, significant funding has been directed by both public research institutions and private pharmaceutical corporations towards the development of drugs that target Ab. Ab is produced by two steps of enzymatic processing: first by b-secretase, and then by g-secretase [5]. The latter has been targeted by drugs collectively known as g-secretase inhibitors, most prominently avagacestat and semagacestat. Both of these drugs failed in Phase 2 and 3 trials, and notably were associated with cognitive decline, an increased risk of skin cancers, and an overall increased risk of serious adverse events [6-10]. It was suspected that the failure of g-secretase inhibitors, particularly with regards to the adverse events profile, was due to off-target inhibition of Notch, a receptor that is involved in a signalling pathway that is particularly prevalent in the skin and gastrointestinal system [9-11]. However, tarenflurbil, a g-secretase modulator that spared the active site of g-secretase and hence spared Notch, also failed to be clinically efficacious, as measured by changes in cognitive indicators such as the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale – cognitive component (ADAS-cog), and the Clinical Dementia Rating – sum of boxes (CDR-sb) [12,13]. Hence, drug development has largely moved away from inhibition of g-secretase, and b-secretase (BACE) inhibitors are now in early development as a potential alternative.

Active and passive immunotherapeutic agents targeting Ab have also been tested, with mixed results. While bapineuzumab was successful in lowering amyloid concentrations in two Phase 3 trials, it did not cause any clinical improvement, compared to placebo, and was associated with the development of amyloid-related imaging abnormalities (ARIA) [14-17]. ARIA comprise two separate changes: vasogenic oedema and cerebral microhaemorrhages. These changes may occur due to destabilisation of amyloid in vascular walls [18,19]. While often asymptomatic, in combination with a lack of clinical efficacy this was sufficient to halt the development of bapineuzumab. Another immunotherapeutic, solanezumab, was underwhelming in its Phase 3 trial performance, but was better tolerated than bapineuzumab and showed some cognitive improvement in patients with mild AD [20-22]. Aducanumab [23], crenezumab [24], and gantenerumab [25] have all also shown promise and currently have Phase 3 trials in planning or underway. Hence, it appears that immunotherapy may be a more viable modality for the treatment of AD than inhibition of g-secretase.

It is possible that all trialled therapeutics have targeted AD too late in the disease course, when clinical features such as memory decline and functional impairments have become frankly apparent. Hence, some trials have now shifted towards targeting AD earlier in its disease course. Mild cognitive impairment (MCI), also known as prodromal AD, is the accepted early pre-AD stage in which it is now believed the greatest improvements can be made, by preventing further decline [26]. Another stage prior to this, subjective cognitive impairment (SCI), in which patients report some cognitive changes but their scores on the MMSE and other indicators are unchanged, is also being recognised and may soon be targeted by therapeutic or preventive strategies [27].

It is also possible, of course, that the current paradigm of the amyloid cascade hypothesis is wrong. Perhaps the drugs have failed to show clinical efficacy, despite reducing cerebrospinal fluid Ab levels, because Ab is not actually central to disease pathogenesis. Another player in the game is tau – a protein that accumulates intracellularly in the classical neurofibrillary tangles. It was originally thought that tau accumulation occurred later in the disease course than that of Ab and was in some way triggered by Ab, supporting the role of Ab accumulation as the primary mediator of disease progression. However, it is now being argued that tau may actually develop concurrently and independently of Ab, and hence this may prove to be a viable target for pharmaceuticals in the future. What is certain, however, is that the pathogenesis of AD is complex, and it is unlikely that engaging with a single target will be sufficient for prevention or a cure [28].

Next year, when AD researchers congregate for AAIC 2017 in London, it is likely that the amyloid cascade hypothesis will further be tested by results from clinical trials of drugs targeting Ab, particularly those of immunotherapeutic agents. Whether there is a significant paradigm shift in terms of our understanding of AD pathogenesis, or a reorientation of our efforts towards prevention over treatment, will largely depend on these results over the next decade. It is certainly important that significant progress is made in the near future, lest pharmaceutical companies that fund drug development put AD in the ‘too hard’ basket and move on to simpler challenges.


Conflicts of interest

None declared



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